The present invention relates generally to methods for reducing or preventing the oxidation of lipids or other molecules, and to methods for inhibiting or reducing microbial proliferation. Specifically, the present invention is directed to compositions and methods for treating oxidative lung injury and other oxidative disorders, and to methods for preventing oxidation of foods, cosmetics and medications. Additionally, the present invention is directed to compositions and methods for treating lung infection and other disorders caused by microbial infection.
The lung is made up of a series of branching conducting airways that terminate in grape-like clusters of delicate gas exchanging airspaces called pulmonary alveoli. Maintenance of alveolar patency at end expiration requires pulmonary surfactant, a mixture of saturated and unsaturated phospholipids and proteins that lines the epithelial surface and reduces surface tension. Surfactant is presented to the oxidizing effects of atmospheric oxygen and inhaled toxicants over a tennis court-sized interface with the environment. The pathophysiological consequences of surfactant oxidation in humans and experimental animals exposed to hyperoxia include airspace collapse, reduced lung compliance and impaired gas exchange.
Air breathing is made possible through the surface tension lowering properties of lung surfactant, an oily film located at the boundary between the aqueous pulmonary epithelial lining fluid (ELF) and the air in the lumen of the alveoli, the gas exchanging distal airspaces of the lung. By weight, surfactant is composed of approximately 50% saturated phospholipids, 40% unsaturated phospholipids and 10% protein, including hydrophilic surfactant proteins A (SP-A) and D (SP-D), and the hydrophobic surfactant proteins B (SP-B) and C (SP-C). After secretion into the ELF, the components of surfactant form membranes at the air-liquid interface which spread readily and compress poorly during cyclical respiratory expansion and contraction.
These properties of surfactant result in enhanced lung compliance during inspiration, which reduces the work of breathing, and very low alveolar surface tension at end expiration, which helps to maintain airspace patency. Exposure of surfactant to ambient oxygen and potent environmental oxidants such as ozone can result in peroxidation of unsaturated phospholipids, surfactant inactivation, airspace collapse and impaired gas exchange. Antioxidant protection of surfactant phospholipids in the ELF has classically been attributed to low molecular mass components urate, ascorbate, and reduced glutathione, and to proteinaceous antioxidants albumin, superoxide dismutase and catalase.
Moreover, after secretion by alveolar type II cells and nonciliated bronchiolar cells into the alveolar lining layer (ALL), the components of surfactant form phospholipid enriched membranes at the air-liquid interface. The surfactant lining has critical surface tension lowering properties which reduce the work of breathing and help to maintain airspace patency. However, the surfactant layer also places a hydrophobic barrier between the inhaled organism and the antimicrobial defenses of the pulmonary epithelium and ALL. In the absence of any specialized defense mechanisms positioned in and around the surfactant membrane, the organism could theoretically proliferate in a microenvironment free from the threat of phagocytic cells, specific antibodies, or innate immune antimicrobial peptides. Without being bound by theory, it is believed that the hydrophilic protein components of the surfactant lining layer, SP-A and SP-D, have potent macrophage independent antimicrobial properties.
The oxidative modifications of surfactant lipids and low density lipoproteins (LDL) and/or microbial proliferation represent key events in the pathogenesis of tissue injury. Thus there is a need for useful therapeutical application of compounds with antioxidant properties and/or antimicrobial properties in the treatment of the inflammatory and hyperoxic lung disease, atherosclerosis, oxidative injury to the skin, and/or lung infection or injury. There is also a need to prevent spoilage, off flavors and off colors due to oxidation and/or microbial proliferation in foods, cosmetics and medications.